Published online before print March 22, 2007, doi: 10.1161/STROKEAHA.106.466268
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(Stroke. 2007;38:1436.)
© 2007 American Heart Association, Inc.
Original Contributions |
Hepatitis B Virus Seropositivity and the Risk of Stroke and Myocardial Infarction
From the Department of Preventive Medicine (J.S.), Kangwon National University College of Medicine, Chunchon, Korea; the Department of Family Medicine (Y.-M.S.) and Center for Health Promotion (Y.-H.C.), Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea; the Department of Epidemiology and Population Health (S.E.), London School of Hygiene and Tropical Medicine, London, England; and the Department of Social Medicine (G.D.S.), University of Bristol, Bristol, England.
Correspondence to Yun-Mi Song, MD, MPH, PhD, Department of Family Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Irwondong, Gangnamgu, Seoul, South Korea. E-mail ymsong{at}smc.samsung.co.kr
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Abstract |
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Background and Purpose— Conflicting findings on the possible association between hepatitis B virus surface antigen (HBsAg) seropositivity and atherosclerosis have been reported. We examined the association between HBsAg seropositivity and cardiovascular diseases in a cohort of Koreans with a high prevalence of hepatitis B viral infection.
Methods— Men (N=521 421) aged 30 to 64 years were categorized into 4 groups according to HBsAg seropositivity status and the presence of liver dysfunction were followed up from 1990 to 2001 for both fatal and nonfatal myocardial infarctions (MIs) and strokes. The associations of HBsAg seropositivity with these cardiovascular diseases were examined with a Cox proportional-hazards model.
Result— Overall, HBsAg seropositivity was associated with a decreased risk of ischemic stroke and MI and an increased risk of hemorrhagic stroke, with multivariable-adjusted hazard ratios (95% CIs) of 0.79 (0.68, 0.90), 0.74 (0.62, 0.87), and 1.33 (1.15, 1.52), respectively. Risks for stroke and MI were similar between HBsAg-seronegative and HBsAg-seropositive men in the absence of liver dysfunction, whereas men with both HBsAg seropositivity and liver dysfunction had a higher risk of hemorrhagic stroke and lower risks of ischemic stroke and MI compared with HBsAg-seronegative men.
Conclusions— The association between HBsAg seropositivity and stroke and MI appears to be secondary to the liver dysfunction associated with hepatitis B viral infection. HBsAg seropositivity itself did not appear to play an important role in atherothrombosis through inducing a proinflammatory effect.
Key Words: cerebral hemorrhage • cerebral infarction • hepatitis B surface antigens • infection • myocardial infarction
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Introduction |
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Substantial experimental and epidemiologic evidence suggests a possible role for infection in the development and progression of atherosclerosis.1–4 However, it is unclear whether atherogenesis is associated with any infection that provokes activation of inflammatory processes or whether only specific organisms play an important role.3,5 Moreover, some studies reporting no association between markers of infection and atherosclerosis cast doubt on their role.6,7
Hepatitis B virus (HBV) infection has several features that make it potentially useful when examining the infection-atherosclerosis hypothesis. First, HBV shares the characteristics of an infectious agent that might be implicated in atherogenesis: HBV is an intracellular pathogen, causes systemic effects and immune responses, and may colonize in the vascular tissues; furthermore, a substantial proportion of those infected in early life go on to develop a chronic phase.8,9 Second, there are well-established and widely used serological markers reflecting the presence and status of infection.10 Third, the pathologic finding of the obliteration of small portal and hepatic veins due to thrombosis and phlebitis associated with the histologic progression to chronic viral hepatitis supports the hypothesis that HBV infection is associated with a thrombotic state.11,12 However, despite these potentially useful characteristics, previous studies of the association of HBV infection with atherosclerosis have reported conflicting findings, making further clarification in a large population study worthwhile.13–15
In this study, we examined the association between HBV surface antigen (HBsAg) seropositivity and major cardiovascular disease (CVD) outcomes, including myocardial infarction (MI) and hemorrhagic and ischemic stroke, in the Korean National Health System (KNHS) cohort, which has considerable statistical power in terms of both the prevalence of markers of HBV infection16 and the number of cardiovascular events to detect relatively small effects. Our hypothesis in this study was that any relation between HBsAg seropositivity and CVDs would depend on the extent of thrombopathic or inflammatory processes associated with HBV infection.
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Subjects and Methods |
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Study Participants
Study participants were Korean male public servants aged 30 to 64 years who underwent a health examination provided by the KNHS between 1986 and 1990. Details have been previously published.17 A total of 755 108 men were examined during this period, of whom 81 978 men changed employment status or experienced an MI or stroke between 1986 and 1990, and 151 709 men lacked data on HBsAg profile, aspartate aminotransferase (AST), alanine aminotransferase (ALT), or cardiovascular risk factor profile. These 233 687 men were excluded from the study, and 521 421 men were finally included in the analysis. Although the excluded men were more likely to be older and have slightly better health behaviors, HBsAg seropositivity and other cardiovascular risk factors were generally comparable between the excluded and included men (data not shown). Women public servants were not included in the study, as there were too few of them and their age distribution was markedly different from that of men. This study was approved by the internal review board of Samsung Medical Center (Seoul, Korea).
Study subjects were divided into 4 groups according to HBsAg status, abnormality of AST and ALT values, and clinical history of liver dysfunction: 275 453 HBsAg-seronegative men with normal transaminase levels and no clinical history of liver dysfunction; 13 902 HBsAg-seropositive men with normal transaminase levels and no clinical history of liver dysfunction; 203 294 HBsAg-seronegative men with abnormal transaminase levels (196 192), a clinical history of liver dysfunction, (1353), or both (5749); and 28 772 HBsAg-seropositive men with abnormal transaminase levels (22 096), a history of liver dysfunction (631), or both (6045).
Measurements
HBsAg seropositivity status was tested by reverse hemagglutination or ELISA. Additional risk factor data were obtained from the biennial multiphasic health examination dataset. Mean levels of fasting serum cholesterol and glucose, weight, and blood pressure measured between 1986 and 1996 were calculated after excluding values obtained after a cardiovascular event. For height, the median value between 1986 and 1996 was selected. Body mass index was calculated as weight divided by height squared. For serum AST and ALT, any increase >40 U/L during the follow-up period was considered to be abnormal; on average, participants had liver function tests repeated 4 times during follow-up. Four categories were constructed for cholesterol (in mmol/L): <4.13, 4.14 to 5.16, 5.17 to 6.20, and 
6.21. Two categories were used for fasting glucose level (in mmol/L) according to the new World Health Organization criteria18: <7.0 or 7.0. Body mass index (in kg/m2) was calculated as weight divided by height squared and was categorized into 4 groups: <18.5, 18.5 to 24.9, 25 to 29.9, and 30.19 Blood pressure (in mm Hg) was classified into 4 groups according to the seventh report of the Joint National Committee on Prevention, Detection, and Treatment of High Blood Pressure20: normal (<120/80), prehypertension (120 to 139/80 to 89), stage 1 hypertension (140 to 159/90 to 99), and stage 2 hypertension (160/100).
We ascertained the history of liver dysfunction (diagnosis of chronic liver disease more than twice at outpatient or inpatient care units) through data linkage by using the health benefit records of the KNHS. The following codes in the tenth revision of the International Classification of Diseases (ICD-10) were used: hepatitis (B180, B181, B189, B19, B190, B199, K73), hepatic cirrhosis (K74), and hepatocellular carcinoma (C22, C220, C227, C228, C229).
Information on health-related behaviors was obtained from a self-administered questionnaire in 1988 and 1990. Smoking habits were classified into 4 groups: never-smoker, ex-smoker, smoking 1 to 19 cigarettes per day, and smoking 20 cigarettes or more per day. For physical exercise, we did not have detailed information, and 2 categories were used: engaging in regular exercise or not. The amount of alcohol consumed (in g/wk) was calculated from the drinking frequency per week and amount per drink and divided into 4 categories: <30, 30 to 104, 105 to 209, and 210. Socioeconomic position was assessed by monthly salary grade and was grouped into 4 categories based on the quartile distribution of monthly salary grade in each age stratum. Area of residence was categorized into 4 groups: capital, large city, medium or small city, and rural area.
Mortality and Morbidity Follow-Up
All nonfatal and fatal MIs and strokes occurring between August 1, 1990 and July 31, 2001 were ascertained through data linkage from the Korean National Statistical Office and the benefit record and hospital admission data of the KNHS. Nonfatal events were defined by the cases who were admitted to hospital for at least 48 hours to exclude those admissions for investigations just to rule out a suspicious cardiovascular diagnosis. Given the easy accessibility to the healthcare system by national health insurance system members and the obligatory death reporting system in Korea, it is likely that almost all cases have been identified. The following codes in the ICD-10 were used: MI (I21-I24), ischemic stroke (I63, I67.8), and hemorrhagic stroke (I61).
Analytical Methods
Follow-up started in August 1990, and the participants were censored at the date of admission or death attributable to stroke, MI, or other causes of death or by July 31, 2001 if no censoring event occurred. Hazard ratios (HRs) for MI, ischemic stroke, and hemorrhagic stroke by 4 HBsAg–liver dysfunction subgroups were estimated by Cox proportional-hazards regression analysis after testing the proportionality assumption, initially in an age-adjusted model and then in a multivariable-adjusted model (conventional cardiovascular risk factors and socioeconomic position adjustments) to examine the independent effects of grouping by HBsAg and liver dysfunction. We examined statistical evidence for an interaction between HBsAg seropositivity and liver dysfunction by including interaction terms (HBsAg seropositivityxliver dysfunction) into regression models.
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Results |
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Of 521 421 men, 2.7% were HBsAg-seropositive without a history of liver disease or abnormal liver function tests, and 5.5% were HBsAg-seropositive with a history of liver disease and/or abnormal liver function tests. During the follow-up of 5 615 054 person-years, 4223 ischemic strokes, 2523 hemorrhagic strokes, and 2998 MIs were registered.
Table 1 compares cardiovascular risk factor profiles and other characteristics of the study participants according to HBsAg seropositivity and the presence or absence of liver dysfunction. Among HBsAg-seropositive men, men with liver dysfunction were more likely to have a higher glucose level, heavier alcohol consumption, obesity, and unfavorable socioeconomic position and were less likely to engage in regular physical exercise than men without liver dysfunction. Compared with the other 3 groups, HBsAg-seronegative men with liver dysfunction had higher glucose, cholesterol, body mass index, and systolic and diastolic blood pressure values and were more likely to be a heavy smoker, heavy drinker, and have a lower pay level.
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Table 2 shows the risk of CVD associated with HBsAg seropositivity status. In multivariable-adjusted analysis, HBsAg-seropositive men had a higher risk of hemorrhagic stroke (HR 1.33, 95% CI 1.15 to 1.52) and lower risks for ischemic stroke (HR 0.79, 95% CI 0.68 to 0.90) and MI (HR 0.74, 95% CI 0.62 to 0.87) compared with HBsAg-seronegative men.
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Table 3 shows the risk of CVD associated with HBsAg seropositivity and liver dysfunction. Multivariable-adjusted analysis showed no strong evidence of any difference in the risks for ischemic and hemorrhagic stroke or MI between HBsAg-seronegative men and HBsAg-seropositive men in the absence of liver dysfunction. Men with both HBsAg seropositivity and liver dysfunction had a higher risk of hemorrhagic stroke and lower risks of ischemic stroke and MI compared with HBsAg-seronegative men. HBsAg-seronegative men with liver dysfunction showed significantly decreased risks for ischemic stroke and MI in all models, but the size of the risk reduction was smaller than that observed in HBsAg-seropositive men with liver dysfunction. Use of higher thresholds of abnormality for liver function tests did not alter the pattern of results (data not shown). The interaction between HBsAg seropositivity and liver dysfunction was statistically significant for ischemic stroke but not for MI and hemorrhagic stroke.
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Discussion |
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In this large cohort study, we found that HBsAg seropositivity was associated with a decreased risk of ischemic stroke and MI and an increased risk of hemorrhagic stroke. However, this association appeared to be secondary to HBV-associated liver dysfunction and did not support the hypothesis that HBV infection itself is associated with an increased risk of MI or ischemic stroke.
Categorizing HBsAg-positive participants into 2 groups by the presence of liver dysfunction allowed the differentiation of any proinflammatory effect of HBV infection itself on CVD risk from the possible anticoagulant effect of liver dysfunction induced secondarily by chronic HBV infection. This latter effect was demonstrated by the higher risk for hemorrhagic stroke and lower risk for MI and ischemic stroke, particularly in those with evident liver dysfunction among the HBsAg-positive men.
Previous studies of the association between HBV and atherosclerosis have reported conflicting findings. A cross-sectional study in Germany reported no association between the risk of atherosclerosis and various serologic markers of HBV infection, including HBsAg as well as anti-HBs.13 However, that German study had some important limitations, especially regarding the adequacy of serologic markers of HBV infection and temporality, given the cross-sectional design. Kiechl et al5 also reported that chronic, active hepatitis B and hepatitis C appeared to be unrelated to the early stage of atherosclerosis as assessed by high-resolution duplex scanning in a 5-year follow-up cohort study. However, diagnostic criteria for chronic active hepatitis B in the study were not clearly described. A study from China14 reported that HBV seropositivity as well as single HBV serologic markers (HBsAg, anti-HBs, HBeAg, anti-HBe, or anti-HBc) were not significantly related to coronary atherosclerosis. An Italian study15 also reported similar findings in patients with chronic, active B and C viral hepatitis, who had a lower prevalence of atherosclerosis of carotid and femoral arteries and the abdominal aorta. Contradictory findings from a study in a Japanese population2 were reported, with a positive association (odds ratio 1.57) between HBsAg positivity and carotid plaque, as identified by high-resolution B-mode carotid ultrasound, independent of other risk factors for atherosclerosis. However, the Japanese study was cross sectional in design, leading to uncertain temporality, and the effect of impaired liver function was not considered.
A proinflammatory effect of infection, measured by markers of inflammation such as C-reactive protein, erythrocyte sedimentation rate, and leukocytes, was suggested as a main pathologic mechanism for the increased risk of atherosclerosis and related disease.21,22 However, a study from China14 that observed no specific association between HBV and coronary artery disease reported that mean C-reactive protein levels were lower in HBV-seropositive than HBV-seronegative individuals.
It could be argued that the null or inverse association between HBV infection and atherosclerosis might be due to a selection bias: those with known, chronic liver disease might adopt healthier lifestyles and receive better health care13 and thereby experience a lower risk of atherosclerosis. Previous negative studies could not address this possibility. In this study, we measured lifestyle factors, and such a selection bias does not seem to have played any important role, as shown in Table 1. It is possible that any cardioprotective effect is secondary to a prolonged infection with HBV rather than the adoption of a healthy lifestyle.23,24
We observed decreased risks for ischemic stroke and MI and increased risks for hemorrhagic stroke among HBsAg-positive men with hepatic dysfunction, which suggests that the anticoagulant effect is stronger than any possible atherogenic effect in chronically HBV-infected persons. In accordance with this interpretation, a previous study exploring the reduced risk of coronary heart disease mortality among HBsAg-positive people found lower levels of clotting factors II and VII and fibrinogen in samples from Gambians and London blood donors who were HBsAg-positive compared with those who were HBsAg-negative.25
The increased risk of hemorrhagic stroke in HBsAg-positive men with liver dysfunction raises the possibility of early-life HBV infection being related to unfavorable childhood socioeconomic conditions, thereby increasing the risk of hemorrhagic stroke.26 In our study, HBV infection was not related to height, which would be expected if HBV infection was related to an adverse childhood socioeconomic position. No correlation was found between adulthood socioeconomic position and HBV infection in our study, but a positive association between HBsAg seropositivity and socioeconomic status in adulthood has been reported by the Korean National Health and Nutrition Survey of 1998.27 Because no increased risk of hemorrhagic stroke was observed in HBsAg-positive men without liver dysfunction, it seems likely that HBsAg-associated chronic liver dysfunction rather than an unfavorable early-life condition is a more plausible explanation for the association with cardiovascular health outcomes in those men with both HBsAg and evidence of liver dysfunction. Low cholesterol level has been suggested as a possible mechanism related to hemorrhagic stroke.28 However, findings from a previous KNHS study showed that the association of low cholesterol levels with increased risk of hemorrhagic stroke was confined to those with a high 
-glutamyl transferase level and high blood pressure, thereby not supporting the causal role for low blood cholesterol.29 Furthermore, HBsAg-positive men with liver dysfunction did not have lower cholesterol levels than the other men in this study.
Our study differs from previous work on HBV infection and atherosclerosis in several aspects. The use of a prospective design and exclusion of individuals who had experienced a study end point before the beginning of the study made the temporality of infection exposure and development of atherosclerosis clear. In the analysis, we were also able to take major cardiovascular risk factors into consideration and examine the effects of HBV infection independently of other risk factors.
The proportion of subjects with abnormal liver function in this study was very high, even among the HBsAg-seronegative persons (42.5%), and it seems to have been caused by our comprehensive criteria for abnormal liver function. To investigate the effect of HBV infection itself independent of the effect of hepatic impairment, we tried to separate all the subjects with any increase in hepatic transaminase levels by checking liver function data for the entire study period. In the Korean National Health and Nutrition Survey of 1998, around 25% of male participants age 30 to 59 had an ALT level >40 U/L.30 Given the relatively higher transaminase level in Korean men and the progressive accumulation of these individuals with abnormal transaminase levels during 11 years, such a high proportion of subjects with abnormal transaminase levels is expected.
Although we wanted to investigate the effect of HBV infection independent of the effect of hepatic impairment and did this by differentiating HBsAg-seropositive men without liver dysfunction from HBsAg-seropositive subjects with liver dysfunction, it is still possible that misclassification occurred, because our methods of diagnosing chronic liver disease would not be capable of detecting subclinical disease. Furthermore, false-positive or false-negative HBsAg readings might be possible. We checked the persistence of HBsAg seropositivity in 87% of all HBsAg-positive study subjects (36 987 men) who were repeatedly tested during the follow-up period, and it was 85.3%. Furthermore, a sensitivity analysis among the participants whose HBsAg test results were unchanged over time showed the same pattern of results (data not shown), suggesting that a bias due to possible misclassification was unlikely. Because we examined HBsAg seropositivity only, this study does not provide any relevant data about the role of more active infection that can be reflected by the presence of HBeAg or HBV DNA. However, even if we had had these data, it would have been difficult to examine our hypothesis further, because active HBV infection is usually accompanied by hepatic impairment and hemostatic dysfunction.
Errors may have been made in assigning the subtype of stroke. However, since the early 1980s, computed tomography has been incorporated into the routine diagnosis of stroke in Korea, and a high rate of neuroimaging can be expected in our study.31 Having focused on clinical end points rather than on underlying pathologic lesions in arteries, we did not gain direct evidence for the HBV infection-atherosclerosis relation. Thus, initiation or progression of the atherogenic process not resulting in a thrombotic event was not assessed, leading to a possible underestimation of any association between HBV infection and atherogenesis.
In conclusion, the associations between HBsAg seropositivity and the risk of stroke and MI appeared to be secondary to HBV-associated liver dysfunction in this cohort study. The findings do not support the hypothesis that HBV infection itself plays an important role in the etiology of MI or ischemic stroke through a proinflammatory effect. Rather, decreased coagulation status in HBV-associated chronic liver dysfunction appeared to increase the risk of hemorrhagic stroke while reducing the risk of ischemic stroke and MI.
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Acknowledgments |
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Sources of Funding
This study was supported by the Ministry of Health and Welfare Korea (No. 01-PJ1-PG1-01CH10-0007). The views expressed in this article are those of the authors and do not necessarily represent any funding body.
Disclosures
None.
Received June 20, 2006; revision received November 21, 2006; accepted November 24, 2006.
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